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V-Maf Musculoaponeurotic Fibrosarcoma Oncogene Homolog A Synthetic Modified mRNA Drives Reprogramming of Human Pancreatic Duct-Derived Cells Into Insulin-Secreting Cells.

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Corritore, Elisa [UCL] Lee, Yong-Syu [UCL] Pasquale, Valentina Liberati, Daniela Hsu, Mei-Ju [UCL] Lombard, Catherine [UCL] Van Der Smissen, Patrick [UCL] Sokal, Etienne [UCL] Lysy, Philippe [UCL]

: β-cell replacement therapy represents the most promising approach to restore β-cell mass and glucose homeostasis in patients with type 1 diabetes. Safety and ethical issues associated with pluripotent stem cells stimulated the search for adult progenitor cells with endocrine differentiation capacities. We have already described a model for expansion and differentiation of human pancreatic duct-derived cells (HDDCs) into insulin-producing cells. Here we show an innovative and robust in vitro system for large-scale production of β-like cells from HDDCs using a nonintegrative RNA-based reprogramming technique. Synthetic modified RNAs for pancreatic transcription factors (pancreatic duodenal homeobox 1, neurogenin3, and V-Maf musculoaponeurotic fibrosarcoma oncogene homolog A [MAFA]) were manufactured and daily transfected in HDDCs without strongly affecting immune response and cell viability. MAFA overexpression was efficient and sufficient to induce β-cell differentiation of HDDCs, which acquired a broad repertoire of mature β-cell markers while downregulating characteristic epithelial-mesenchymal transition markers. Within 7 days, MAFA-reprogrammed HDDC populations contained 37% of insulin(+) cells and a proportion of endocrine cells expressing somatostatin and pancreatic polypeptide. Ultrastructure analysis of differentiated HDDCs showed both immature and mature insulin granules with light-backscattering properties. Furthermore, in vitro HDDC-derived β cells (called β-HDDCs) secreted human insulin and C-peptide in response to glucose, KCl, 3-isobutyl-1-methylxanthine, and tolbutamide stimulation. Transplantation of β-HDDCs into diabetic SCID-beige mice confirmed their functional glucose-responsive insulin secretion and their capacity to mitigate hyperglycemia. Our data describe a new, reliable, and fast procedure in adult human pancreatic cells to generate clinically relevant amounts of new β cells with potential to reverse diabetes.

Document type Article de périodique (Journal article) – Article de recherche
Access type Accès libre
Publication date 2016
Language Anglais
Journal information "Stem Cells Translational Medicine" - Vol. 5, no. 11, p. 1525-1537 (2016)
Peer reviewed yes
Publisher Wiley Periodicals, Inc. on behalf of AlphaMed Press ((United States) Hoboken, NJ)
issn 2157-6564
e-issn 2157-6580
Publication status Publié
Affiliations UCL - SSS/IREC/PEDI - Pôle de Pédiatrie
UCL - (SLuc) Service de gastro-entérologie et hépatologie pédiatrique
UCL - (SLuc) Service d'endocrinologie et diabétologie pédiatrique
Links
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Bibliographic reference Corritore, Elisa ; Lee, Yong-Syu ; Pasquale, Valentina ; Liberati, Daniela ; Hsu, Mei-Ju ; et. al. V-Maf Musculoaponeurotic Fibrosarcoma Oncogene Homolog A Synthetic Modified mRNA Drives Reprogramming of Human Pancreatic Duct-Derived Cells Into Insulin-Secreting Cells.. In: Stem Cells Translational Medicine, Vol. 5, no. 11, p. 1525-1537 (2016)
Permanent URL http://hdl.handle.net/2078.1/175761